sirolimus and Neurogenic-Inflammation

Autophagy is an intracellular catabolic mechanism essential for recycling intracellular unfolding protein and eliminating toxic protein aggregates. Several studies have shown that deficient autophagy is implicated in the development of Alzheimer's disease (AD) progression. To date, rapidly emerging evidence suggests that neurosteroid progesterone (PG) may play an important role in ameliorating AD. However, the role of PG and its neuroprotective mechanism in regulating autophagy still require further investigation. Here, we investigated the protective effects of PG against Aβ-induced inflammatory responses in astrocytes and its underlying mechanism in mediating autophagy. Remarkably, Aβ induced astrocyte dysfunction in autophagic activation and up-regulated inflammatory secretion. However, the autophagy inducer rapamycin (RAPA) significantly suppressed Aβ-induced inflammation in astrocytes. In astrocytes, treatment with Aβ caused autophagy deficiency, whereas PG significantly increased autophagy activation. Finally, PG suppressed Aβ-induced neuroinflammatory production via enhancing autophagy together with regulating mTOR signaling. Taken together, these results show that autophagy is a vital mechanism against Aβ-induced neuroinflammatory responses in astrocytes and demonstrate the potential neuroprotective mechanism of PG in suppressing neuroinflammatory responses by enhancing autophagy. Therefore, uncovering the neuroprotective mechanism of PG may provide new insight into novel therapies for the amelioration of AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Astrocytes; Autophagy; Cells, Cultured; Humans; Neurogenic Inflammation; Peptide Fragments; Progesterone; Protein Aggregation, Pathological; Rats; Rats, Sprague-Dawley; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

Protein translation controlled through activation of mammalian target of rapamycin (mTOR) participates in many physiological and pathological processes. However, whether such activation is required for chronic pain is still unknown. Here, we examined activation of the mTOR signaling pathway during complete Freund's adjuvant (CFA)-induced chronic inflammatory pain and L5 spinal nerve ligation (SNL)-induced neuropathic pain in rats. Western blot analysis showed significantly increased levels of phosphorylated mTOR (p-mTOR) and phosphorylated p70S6 kinase 1 (p-S6K1, a downstream effector of mTOR) in the ipsilateral L4/5 spinal cord 2h, 1 day, 3 days, and 7 days after intraplantar CFA injection and in the ipsilateral L4/5 dorsal root ganglions (DRGs) 1 and 3 days after CFA injection. Immunohistochemistry also demonstrated increases in number of p-mTOR-labeled neurons in the ipsilateral L4/5 DRGs and in density of p-mTOR-labeled immunoreactivity in the ipsilateral L4/5 superficial dorsal horn 1 day after CFA injection. Moreover, intrathecal administration of rapamycin, a selective inhibitor of mTOR, significantly blocked CFA-induced mechanical allodynia and thermal hyperalgesia 1 day post-CFA injection. Interestingly, expression of neither p-mTOR nor p-S6K1 was markedly altered on days 3, 7, or 14 after L5 SNL in L5 spinal cord or DRG. These findings indicate that in DRG and spinal cord, mTOR and S6K1 are activated during chronic inflammatory pain, but not during neuropathic pain. Our results strongly suggest that mTOR and its downstream pathway contribute to the development of chronic inflammatory pain.

Topics: Animals; Disease Models, Animal; Freund's Adjuvant; Functional Laterality; Ganglia, Spinal; Gene Expression Regulation; Hyperalgesia; Immunosuppressive Agents; Male; Neuralgia; Neurogenic Inflammation; Pain Measurement; Pain Threshold; Rats; Rats, Sprague-Dawley; Ribosomal Protein S6 Kinases; Signal Transduction; Sirolimus; Spinal Cord; Spinal Nerves; Statistics, Nonparametric; Time Factors; TOR Serine-Threonine Kinases